Mitochondria play a central role in the energy homeostasis of the cell and the whole animal. PGC-1a and PGC-1beta are proteins that powerfully regulate mitochondrial activity. Recent data suggest that human type 2 diabetes is associated with lower activity of mitochondria and of the PGC-1 proteins in skeletal muscle. These observations strongly suggest that stimulating PGC-1a expression or activity may have important beneficial effects in type 2 diabetes and obesity. We propose here to identify chemical compounds that can modulate the PGC-1 proteins and mitochondrial function in both cells and animals. We will utilize chemical libraries that include a large number of FDA-approved drugs and other known bioactives, as well as novel highly diverse chemical libraries produced at the Broad Institute in Cambridge. We will use two different assays. The first, based on quantitative real-time PCR, will detect induction of PGC-1 gene expression. The second, based on activation of a PGC-1a fusion protein that drives a luciferase gene, will detect direct activation of the PGC-1a protein. Compounds identified using these assays will then be evaluated for their effects on glucose homeostasis, insulin resistance, and mitochondrial biology in cells and in well- established animal models of obesity, insulin resistance and type 2 diabetes. The goals of these studies are two-fold: first, to develop a robust high-throughput assay to discover compounds that can modify mitochondrial and PGC-1 activity; and second, to establish proof of concept that chemical manipulations of these systems can have a benefit in obesity and type 2 diabetes. [unreadable]